Gene Variability and Vulnerability to Alcoholism.

Variability within genes may explain why so many differences in alcoholism exist between individuals and among populations. Researchers studying this phenomenon have focused on genes that may affect both the way the body metabolizes alcohol and the way the brain responds to alcohol, thereby increasing or decreasing the likelihood of addiction. Gene variants may ultimately be used as markers of alcoholism vulnerability and as guides to help match patients to the most appropriate alcoholism therapies.


GENES FOR ALCOHOL
orders such as Huntington's disease, 1 behav METABOLISM ioral traits appear to be influenced by the interaction of several genes, each of which Alcohol is metabolized in the liver by two

GENES RELATED TO NERVE
may exert only a small effect (Plomin 1990). enzymes acting sequentially. First, alcohol

CELL COMMUNICATION
Social, cultural, and other nongenetic in dehydrogenase (ADH) converts alcohol to a fluences interact with genetic vulnerability chemical called acetaldehyde. Acetaldehyde, All brain activity results from communi to cause alcoholism (Devor 1993).
in turn, is converted to acetate by aldehyde cation between nerve cells. Alcoholism Despite the importance of nongenetic dehydrogenase (ALDH) (Goldman and researchers have concentrated on the influences, however, the disease of alco Enoch 1990). Acetaldehyde is a toxic sub pathways of nerve cell communication holism always occurs within a matrix of stance that may be partially responsible for most likely to assist in regulating alcohol genetically determined mechanisms that some of the adverse medical consequences consumption and promoting alcoholism. differ between individuals and between of alcohol consumption (Lieber 1994). Among these are pathways that use the populations. The basis for these differences After consuming alcohol, certain Asian neurotransmitters 3 dopamine and serotonin is polymorphism, the existence of one or populations experience facial flushing, pal as well as the endogenous opioids. more variant forms (i.e., alleles) of the pitations, headache, dizziness, and nausea. same gene. These inborn genetic differ The flushing reaction is associated primari Dopamine ences serve as a starting point for under ly with a defective variant of ALDH that standing the web of interactions that lead allows the accumulation of acetaldehyde in Dopamine is a neurotransmitter whose to alcoholism (Goldman 1995).
the blood and tissues after alcohol con many functions include facilitating learn Various methods exist for testing the sumption (Thomasson et al. 1993 central to developing addiction to alcohol and other drugs (AOD's) (Di Chiara 1995). Dopamine Metabolism. Dopamine re leased into a synapse binds rapidly to its receptors and is transported quickly back into the nerve cell that released it (i.e., re uptake). Following reuptake, some dopa mine is stored for subsequent rerelease; the rest is metabolized by the enzyme monoamine oxidase (MAO). This enzyme occurs in two forms, or isoenzymes: MAO-A and MAO-B, which are encoded by two similar but distinct genes located close together on the same chromosome.
The precise roles of the two isoenzymes have not been fully clarified, although both MAO-A and MAO-B can metabolize dopamine. Lowered MAO-B activity has been detected frequently among alcoholics and their close relatives, compared with higher MAO-B activity among nonalco holics. This difference could be attributed to polymorphism within the MAO-B gene. Such polymorphism may represent varia tion in the DNA sequence that codes for the enzyme's structure or in the DNA sequence that regulates the gene's activity . In either case, if varia tion in MAO-B activity can be related to specific DNA sequence variation within the MAO-B gene, the altered DNA sequence might serve as a genetic marker to help identify persons at risk for alcoholism ). 4 Dopamine Receptors. Five types of dopa mine receptors have been identified in the brain and have been designated D 1 through D 5 . Although all five receptors respond to dopamine, their specific properties and functions differ slightly from one another (Mansour et al. 1995). The dopamine re ceptor D 2 plays a role in reinforcement, a key component of the process by which a behavior, such as alcohol consumption, becomes habitual (Di Chiara 1995). In 1990, Blum and colleagues reported a strong population association 5 between alcoholism and a specific allele (A1) of the gene that directs the synthesis of D 2 (the gene is known as DRD 2 ). Specifically, researchers observed allele A1 of DRD 2 more frequently in a group of alcoholics compared with a group of nonalcoholic subjects (i.e., controls) (for a discussion of population association methods, see the article by Goate, pp. 217-220).
Subsequent research found this popula tion association to be much weaker than originally reported (Parsian et al. 1991;Blum et al. 1991Blum et al. , 1993 or failed to find an association at all (Goldman et al. 1992Gelernter 1993;Cook et al. 1992). In addition, Gejman and colleagues (1994) examined the DNA sequence of DRD 2 from large samples of alcoholics and schizophrenics and detected no variation in the coding segment of the gene that could account for an association with alcoholism.
Spurious results in population associa tion studies may result from failure to match test subjects adequately to controls for ethnicity or other factors that may affect overall genetic composition. Significantly, in this regard, studies conducted in ethni cally welldefined populations have gener ally failed to show an association between DRD 2 and alcoholism (Goldman et al. 1992;Arinami et al. 1993). According to Goldman and colleagues (1993), differences in DRD 2 polymorphism among diverse populations are sufficient to account for spurious popu lation associations or, conversely, to ob scure such associations that may exist.
Despite the failure to replicate the initial research on DRD 2 , the central role dopamine plays in the addiction process ensures that research on dopamine recep tor genes will continue. Researchers have reported associations between DRD 2 and alcoholismrelated phenomena (Comings et al. 1991), including drug abuse (Smith et al. 1992;Noble 1993) and aberrations of brain electrical activity . Variation also has been detected in the D 3 (Rietschel et al. 1993) and D 4 (Lichter et al. 1993) receptors, although the significance of this finding is unclear.

Serotonin
Many investigators believe that alco holism is related to the levels in the brain of the neurotransmitter serotonin (Litten and Allen 1991). Serotonin helps regulate such functions as bodily rhythms, food and water intake, sexual response, and aggression. Brain serotonin concentrations, which are difficult to measure directly, can be estimated by measuring the con centration in cerebrospinal fluid (CSF) 6 of 5hydroxyindoleacetic acid (5-HIAA), a product of serotonin metabolism. Re duced brain serotonin function, as indicated by low CSF 5-HIAA concentration, is associated with increased risk of violent behavior, suicide, depression, and alco holism among people with psychiatric disorders as well as the general population (reviewed in Pihl and Peterson 1993). These manifestations appear to be causally related: The presence of one appears to increase the risk for any or all of the others (reviewed in in Tollefson 1995). In addition, alco holism and other problems involving im pulsive behavior appear to be inherited together in families (Cloninger et al. 1985;Bohman 1978).
Family studies suggest that genetic polymorphism influences the function of serotonin and its receptors. Therefore, re searchers are attempting to identify specific alleles that may influence vulnerability to alcoholism or behaviors that may be asso ciated with alcoholism (Nielsen et al. 1994;Virkkunen et al. 1994a,b).

Genes for Serotonin Synthesis and
Metabolism. Variations in serotonin levels and activity among different populations may be caused by polymorphism in genes that control serotonin synthesis and meta bolism. Many of the genes potentially important in controlling serotonin meta bolism have been cloned, including the gene that codes for the enzyme tryptophan hydroxylase (TPH) (Nielsen et al. 1994). TPH initiates the synthesis of serotonin from tryptophan, a chemical found in food. An allele of the TPH gene has been associated with low CSF 5-HIAA concen trations along with suicidal behavior among a group of alcoholic prisoners in carcerated in Finland for criminal offenses involving impulsivity (Nielsen et al. 1994). However, Abbar and colleagues (1995) did not find an association between TPH polymorphism and suicidal behaviors among patients in a French hospital.
MAO-A, discussed previously with re spect to dopamine, also metabolizes sero tonin. In a study of a single large family, researchers linked deficient enzymatic activity of MAO-A to a minor alteration in the DNA sequence of the MAO-A gene. Behavioral manifestations included bor derline mental retardation, impulsive aggression, arson, attempted rape, and exhibitionism. This symptom cluster does not specifically include alcoholism and has not yet been reported in other popula tions (Brunner et al. 1993;Goldman 1995).
The genes for both MAO-A and MAO-B have been cloned (reviewed in Nielsen et al. 1994). However, both genes are on the female sex (i.e., X) chromosome. Because a high percentage of alcoholism is transferred from father to son, it is unlikely that genes located on the X chromosome account for more than a small fraction of the genetic vulnerability to alcoholism; nonetheless, MAO-A and MAO-B gene polymorphisms could be involved in the genetic liability of a subgroup of alcoholics (Goldman 1995).
Also cloned are the gene for aromatic Lamino acid decarboxylase (SumiIchinose et al. 1992), another enzyme involved in serotonin synthesis, and the gene for the serotonin transporter, a protein in the nerve cell membrane involved in serotonin reup take (Hoffman et al. 1991). Effects on alcoholism of possible polymorphisms at these genes have not been established.

Genes for Serotonin Receptors.
Researchers have identified seven major classes of serotonin receptors, designated 5HT 1 through 5HT 7 (Grant 1995). These families have been further divided into subtypes, at least eight of which have been cloned (Goldman 1995). Receptor 5HT 3 plays a role in the acute and chronic ef fects of AOD's on the nervous system and also has been implicated in psychiatric illnesses such as schizophrenia, anxiety, and Alzheimer's disease (Grant 1995). When activated by serotonin, 5HT 3 func tions to regulate communication along nerve cell pathways by influencing the release of certain neurotransmitters into synapses. Among the neurotransmitters regulated by 5HT 3 is dopamine, discussed previously. Researchers have suggested that the direct action of alcohol on 5HT 3 leads to increased dopamine activity in areas of the brain involved in reinforce ment, potentially contributing to the devel opment of addiction behaviors (Johnson and Cowen 1993;Grant 1995). Researchers are studying variations of other serotonin receptor genes for possible associations with alcoholism (Blanchard et al. 1992;Lappalainen et al. 1995).

Genes Related to Endogenous Opioids
Endogenous opioids are neurotransmitters in the human nervous system that produce effects similar to those of morphine and other opiates. Evidence suggests that alcoholinduced activation of the endoge nous opioid system may affect alcohol reinforcement and drinking behavior (Froehlich 1995). This theory is supported by the effectiveness of naltrexone, an opiate antagonist, in helping prevent re lapse in patients being treated for alco holism (Volpicelli et al. 1992). Animal studies suggest that a genetic predisposition toward alcohol consumption may be accom panied by increased responsiveness of the endogenous opioid system to alcohol (De Waele et al. 1992). In one study, alcohol consumption produced a significant in crease in blood levels of betaendorphin in subjects with significant family histories of alcoholism, but not in families without histories of alcoholism. The mechanism of this difference is unknown, although the results indicate that the basis of the differ ence is genetic (Gianoulakis et al. 1989).

CONCLUSIONS
The causes and manifestations of alco holism may differ significantly among individuals. Apart from environmental influences, multiple genes may each con tribute to the disorder, and some re searchers have suggested that certain families may have their own unique mix ture of genes responsible for alcoholism vulnerability (Plomin 1990).
Population and molecular biology studies among humans will continue to shed light on the disorder. Animal studies will provide additional evidence, for ex ample, by mapping quantitative trait loci (QTL), genes that together contribute to an effect although their individual effects may be minuscule. By studying QTLs in rodents, researchers may help identify genes that should be studied in humans. QTLs have been identified provisionally for alcohol withdrawal, alcohol prefer ence, and alcohol sensitivity; evidence indicates that QTLs may be under com mon genetic control (Crabbe et al. 1994; also see the article by Grisel and Crabbe,. New directions for genetic analysis may be suggested by results of the Collaborative Study on the Genetics of Alcoholism (COGA). This comprehensive program, involving six research centers across the United States, is investigating the genetic contribution to alcoholism vulnerability. Final analysis of COGA data may reveal potential alcoholism related genes unrelated to any genes previ ously thought relevant to alcoholism. (See the article on COGA, Future study of genetic variants also might focus on some of the more specific and directly heritable alcoholismrelated traits, such as variants of brain electrical activity (Enoch et al. in press). Ultimately, gene variants may be used as markers of alcoholism vulnerability and as guides to help match patients to appropriate alco holism therapies (Goldman 1995). ■